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Circadian regulation of prefrontal cortex dependent emotional memories

前额叶皮层依赖性情绪记忆的昼夜节律调节

基本信息

批准号：
10540714
负责人：
ROBERT L SPENCER
金额：
$ 39.82万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540714
关键词：
Acute Amygdaloid structure Animal Model Animals Anxiety Disorders Auditory Behavior Control Behavioral Bipolar Disorder Brain region Cell physiology Cells Circadian Dysregulation Circadian Rhythms Clinical Cognitive Corticosterone Development Disease Effectiveness Electrophysiology (science)Elements Emotional Ensure Extinction FRAP1 gene Female Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Glucocorticoids Hormone secretion Hormones Human Hypothalamic structure Impairment Individual Learning Major Depressive Disorder Manic Measures Medial Mediating Memory Mental Depression Mental disorders Moods Morphology Neural Pathways Neuroanatomy Neuronal Plasticity Neurons Neuropsychology Pattern Performance Periodicity Peripheral Phase Physiologic pulse Physiological Physiological Processes Play Post-Traumatic Stress Disorders Prefrontal Cortex Process Prosencephalon Rattus Research Resolution Role Schizophrenia Signal Pathway Signal Transduction System Testing Therapeutic Time Tissues Training Translating Vertebral column Viral Work body system cell growth regulation circadian circadian pacemaker circadian regulation clinically relevant conditioned fear effective therapy experimental study improved in vivo innovation insight knock-down learning extinction male molecular clock neural neural circuit neurobiological mechanism neuromechanism novel therapeutic intervention optogenetics pre-clinical response stress related disorder suprachiasmatic nucleus treatment of anxiety disorders virtual

项目摘要

Psychiatric disorders, especially those marked by dysregulated mood and emotional control, such as depression, bipolar disorder, post traumatic stress disorder (PTSD) and schizophrenia, are associated with physiological and cognitive features of disrupted circadian function. Circadian regulation is necessary for appropriate anchoring of the optimal performance of virtually every cell and system of the body to fluctuating daily demands. Although the suprachiasmatic nucleus (SCN) of the hypothalamus serves as the body’s master circadian pacemaker, cells in other brain regions and in peripheral tissues express many of the same molecular clock elements (i.e. clock genes) as those found in the SCN. Recent advances have been made in determining the functional role and regulation of cellular clocks in peripheral tissues. Those studies demonstrate an important circadian entraining influence of the endogenous glucocorticoid hormones (CORT) on peripheral tissue cellular clock function. However, there is very little understanding of the function and regulatory processes of cellular clocks in extra-SCN brain regions. The prefrontal cortex (PFC) is a brain region that plays a central role in organizing and coordinating physiological, behavioral and emotional responses. Animal and human studies show that there is rhythmic clock gene expression in the PFC. Recent studies have found that normal clock gene expression in the PFC of rats depends on appropriate profiles of CORT secretion. Moreover, disruption of CORT-entrained PFC clock gene expression results in impaired diurnal patterns of conditioned fear extinction memory. PTSD is associated with impaired circadian function, compromised PFC function and dysregulation of CORT secretion. In addition, individuals with PTSD suffer from persistent conditioned fear responses. Improving conditioned fear extinction learning is a primary therapeutic objective for treating PTSD. Consequently, this project will use a rat animal model to determine the mechanistic basis by which PFC clock gene expression and CORT interdependently regulate conditioned fear extinction memory. The project is organized around 3 specific aims: Aim 1] To determine how time of day, circadian CORT and ventral medial PFC (vmPFC) clock gene expression modulate the activity of neuronal projections from the vmPFC to the basal medial amygdala (BMA) during conditioned fear extinction training and recall. Aim 2] To determine how time of day, circadian CORT and vmPFC clock gene expression modulate neuroplasticity- related processes in the vmPFC that support conditioned fear extinction recall. Aim 3] To test the necessity and sufficiency of vmPFC to BMA projections for mediating time of day, circadian CORT and vmPFC clock gene expression regulation of conditioned fear extinction recall. The proposed studies will provide new understanding of how circadian and CORT factors dynamically interact to regulate PFC function. These studies will also lead to better understanding of the underlying mechanisms of conditioned fear extinction memory, a neuroprocess that has important clinical relevance for circadian and stress-related disorders.

精神疾病，特别是那些以情绪和情绪控制失调为特征的疾病，例如抑郁症、双相情感障碍、创伤后应激障碍 (PTSD) 和精神分裂症与昼夜节律功能紊乱的生理和认知特征。昼夜节律调节是必要的适当锚定身体几乎每个细胞和系统的最佳性能以应对波动日常需求。虽然下丘脑的视交叉上核（SCN）是身体的主宰昼夜节律起搏器，其他大脑区域和周围组织的细胞表达许多相同的分子时钟元件（即时钟基因）如 SCN 中发现的那些。最近在以下方面取得了进展确定外周组织中细胞时钟的功能作用和调节。那些研究证明内源性糖皮质激素 (CORT) 具有重要的昼夜节律影响对周围组织细胞时钟功能的影响。但对其功能了解甚少 SCN 外大脑区域细胞时钟的调节过程。前额皮质 (PFC) 是大脑的一个区域它在组织和协调生理、行为和情绪反应方面发挥着核心作用。动物和人类研究表明前额皮层中存在节律时钟基因表达。最近的研究有发现大鼠 PFC 中正常的时钟基因表达取决于 CORT 分泌的适当分布。此外，CORT 引起的 PFC 时钟基因表达的破坏会导致昼夜模式受损。条件性恐惧消退记忆。 PTSD 与昼夜节律功能受损、PFC 受损有关 CORT 分泌的功能和失调。此外，患有创伤后应激障碍（PTSD）的人会遭受持续的条件性恐惧反应。改善条件性恐惧消退学习是主要治疗目标治疗创伤后应激障碍。因此，该项目将使用大鼠动物模型来确定机械基础其中PFC时钟基因表达和CORT相互依赖地调节条件性恐惧消退记忆。该项目围绕 3 个具体目标进行组织：目标 1] 确定一天中的时间、昼夜节律 CORT 和腹侧内侧 PFC (vmPFC) 时钟基因表达调节神经元投射的活动在条件性恐惧消退训练和回忆过程中，vmPFC 与基底内侧杏仁核 (BMA) 的关系。目标 2] 到确定一天中的时间、昼夜节律 CORT 和 vmPFC 时钟基因表达如何调节神经可塑性 vmPFC 中支持条件性恐惧消退回忆的相关过程。目标 3] 测试必要性 vmPFC 到 BMA 预测的充分性，用于调节一天中的时间、昼夜节律 CORT 和 vmPFC 时钟条件性恐惧消退回忆的基因表达调控。拟议的研究将提供新的了解昼夜节律和 CORT 因素如何动态相互作用以调节 PFC 功能。这些研究还将导致更好地理解条件性恐惧消退记忆的潜在机制，与昼夜节律和压力相关疾病具有重要临床相关性的神经过程。